Research database

Research summary

Mouse studies show restored vision, muscle and cognitive function; Altos Labs, Retro Biosciences and NewLimit pursuing translation. No human data yet.

Limitations

Teratoma risk with sustained expression; delivery, dosing and tissue selectivity unresolved; no human trials.

Biomarker targets

• DNAm age
• Horvath clock

Key references

• Lu et al., Nature 2020 — Reprogramming to recover youthful epigenetic information

Research summary

Extended median lifespan in mice without raising cancer incidence in the original study; human use remains investigational and largely unregulated.

Limitations

Theoretical oncogenic risk; durability and dosing unknown; human evidence limited to small unregulated cohorts.

Biomarker targets

• Telomere length

Key references

• Bernardes de Jesus, EMBO Mol Med 2012 — Telomerase gene therapy extends mouse lifespan

Research summary

VERVE-101/-102 early-phase human data show durable LDL reduction — a proof of concept for one-and-done cardiovascular risk reduction relevant to healthspan.

Limitations

Long-term off-target and durability data maturing; targets a risk factor, not aging itself; access and cost.

Biomarker targets

• ApoB
• LDL-C
• Lp(a)

Key references

• Lee et al., Circulation 2022 — Preclinical CRISPR base editing of PCSK9 (VERVE-101); first-in-human Heart-1 interim data 2023

Research summary

Robust muscle-preserving effects in animal models; human use confined to small experimental programs.

Limitations

No controlled human longevity data; regulatory and safety oversight limited.

Biomarker targets

• Lean mass
• Grip strength

Research summary

Higher Klotho associates with longevity and cognition in humans; delivery approaches (gene therapy, secretagogues) are preclinical.

Limitations

Causality in humans unproven; no validated way to durably raise Klotho clinically.

Biomarker targets

• α-Klotho
• Cystatin C

Research summary

Rapid clinical progress in targeted indications (transthyretin amyloidosis, NTLA-2001) proves durable in-vivo editing is feasible; broad aging application remains aspirational.

Limitations

Off-target edits; delivery beyond the liver; immunogenicity; no aging-endpoint programs yet.

Biomarker targets

• Target-gene expression

Key references

• Gillmore et al., NEJM 2021 — In-vivo CRISPR editing for ATTR amyloidosis

Research summary

Preclinical strategies restore mitochondrial function in models; human use is confined to rare primary mitochondrial diseases.

Limitations

mtDNA delivery is technically hard; heteroplasmy control; no aging trials.

Biomarker targets

• mtDNA copy number
• NAD+/NADH

Research summary

A single uPAR-directed CAR-T dose cleared senescent cells and improved metabolic and fibrotic endpoints in mice, with lasting effect.

Limitations

Cytokine-release and on-target/off-tumor toxicity; entirely preclinical for aging.

Biomarker targets

• uPAR
• SASP panel

Key references

• Amor et al., Nature 2020 — Senolytic CAR T cells reverse senescence pathologies

Research summary

Predominantly animal studies show promise for FOXO3 overexpression. Human clinical applications remain theoretical.

Limitations

No human trials completed; delivery mechanisms under development; long-term effects unknown

Biomarker targets

• Insulin sensitivity
• Oxidative stress
• DNA repair

Research summary

Animal models show metabolic improvements and lifespan extension. Human translation in early development.

Limitations

Tissue-specific expression challenges; optimal dosing unclear; metabolic side effects possible

Biomarker targets

• NAD+ levels
• Mitochondrial biogenesis
• Metabolic function

Research summary

Animal studies demonstrate enhanced mitochondrial function and exercise capacity. Human applications theoretical.

Limitations

Delivery to target tissues challenging; exercise interaction effects unknown; safety profile developing

Biomarker targets

• Mitochondrial density
• VO2 max
• Metabolic efficiency
• Exercise capacity

Research summary

Human FGF21 analogs show metabolic benefits. Gene therapy approaches aim for sustained expression.

Limitations

Duration of expression variable; injection site reactions; optimal target tissues unclear

Biomarker targets

• Glucose metabolism
• Lipid profiles
• Weight management
• Insulin sensitivity

Research summary

Small human pilots (IPF, diabetic kidney disease) show reduced senescent-cell burden and SASP markers with intermittent 'hit-and-run' dosing.

Limitations

Limited long-term human data; bleeding and cytopenia considerations; optimal dose/schedule undefined.

Biomarker targets

• p16INK4a
• IL-6
• GDF-15

Key references

• Justice et al., EBioMedicine 2019 — First-in-human senolytics pilot in IPF

Research summary

Extended healthspan/lifespan in aged mice; Mayo Clinic AFFIRM-LITE and related human trials underway.

Limitations

Bioavailability limits; human efficacy not yet established; supplement-grade quality varies.

Biomarker targets

• p16INK4a
• SA-β-gal
• hs-CRP

Key references

• Yousefzadeh, EBioMedicine 2018 — Fisetin is a senotherapeutic that extends health/lifespan

Research summary

UNITY Biotechnology reported sustained vision gains in diabetic macular edema — a localized proof of concept for senolysis.

Limitations

Local (ocular) delivery; systemic senolysis unproven by this route; single-indication data.

Biomarker targets

• Retinal thickness
• VEGF

Key references

• UNITY Biotechnology BEHOLD study — UBX1325 in DME

Research summary

Effective senescent-cell clearance in animals; oncology-derived, so aging use is constrained by platelet toxicity.

Limitations

Thrombocytopenia limits chronic use; not suited to healthy-aging populations at current doses.

Biomarker targets

• Platelet count
• p16INK4a

Research summary

Proof of concept in mice reduced senescent burden and improved metabolic and vascular endpoints.

Limitations

Antigen specificity and autoimmunity risk; entirely preclinical.

Biomarker targets

• GPNMB
• SASP panel

Research summary

Mouse studies show PCC1 selectively kills senescent cells at high concentrations while inhibiting SASP at lower doses. Extends lifespan and improves physical function in aged mice. Natural compound with favorable safety profile.

Limitations

Only animal data; optimal human dosing unknown; bioavailability of procyanidins varies; long-term effects unstudied

Biomarker targets

• p16INK4a
• SASP factors
• Senescent cell burden
• Physical function

Research summary

Decades of human safety data; the TAME trial is designed to test whether it delays age-related disease in non-diabetics. Some data suggest it may blunt exercise adaptations.

Limitations

GI intolerance; B12 depletion; renal dosing; non-diabetic longevity benefit still unproven pending TAME.

Biomarker targets

• HbA1c
• Fasting insulin
• IGF-1

Key references

• Barzilai et al., Cell Metab 2016 — Metformin as a Tool to Target Aging

Research summary

CALERIE-2 RCT showed reduced biological aging pace (DunedinPACE) and improved cardiometabolic risk in non-obese humans over 2 years.

Limitations

Adherence is difficult; risk of lean-mass and bone loss; not appropriate for underweight or frail individuals.

Biomarker targets

• IGF-1
• DunedinPACE
• hs-CRP

Key references

• CALERIE-2, Waziry et al., Nat Aging 2023 — CR slows pace of aging in humans

Research summary

Large RCTs show cardiovascular, renal and heart-failure benefit; canagliflozin extends male mouse lifespan in the ITP, prompting aging interest.

Limitations

Euglycemic ketoacidosis and genito-urinary infection risk; direct human aging trials pending.

Biomarker targets

• eGFR
• Cystatin C
• NT-proBNP

Key references

• Miller et al., 2020 (ITP) — Canagliflozin extends male mouse lifespan

Research summary

Robust RCTs (SELECT, cardiovascular and renal outcome trials) show reduced events; healthspan relevance strong, direct aging trials emerging.

Limitations

GI effects; lean-mass loss without resistance training; long-term aging endpoints not yet measured.

Biomarker targets

• HbA1c
• Body composition
• hs-CRP

Key references

• SELECT trial, NEJM 2023 — Semaglutide and cardiovascular outcomes

Research summary

Superior metabolic outcomes compared to single agonists. Aging applications under investigation.

Limitations

Higher cost; injection complexity; long-term safety profile developing

Biomarker targets

• Weight management
• Insulin sensitivity
• Lipid metabolism
• Hepatic function

Research summary

Intermittent low-dose regimens studied in humans (PEARL) for healthspan and immune function; extends lifespan in the NIA Interventions Testing Program.

Limitations

Immunosuppression, glucose intolerance and mouth ulcers at higher/continuous doses; optimal human protocol unsettled.

Biomarker targets

• mTOR activity
• Fasting glucose
• Immune markers

Key references

• Harrison et al., Nature 2009 — Rapamycin extends lifespan in genetically heterogeneous mice

Research summary

Strong, reproducible rodent lifespan data; human evidence extrapolated from diabetes and glycemic-variability outcomes.

Limitations

GI side effects (flatulence, bloating); human aging endpoints not directly tested.

Biomarker targets

• Postprandial glucose
• HbA1c

Key references

• NIA Interventions Testing Program — Acarbose lifespan extension

Research summary

Observational and small human trials suggest cognitive and cardiovascular benefit; extends lifespan across model organisms.

Limitations

Confounded observational data; RCT efficacy modest and preliminary.

Biomarker targets

• Autophagy markers
• Cognitive scores

Key references

• Eisenberg et al., Nat Med 2016 — Spermidine and cardioprotection

Research summary

Similar mechanism to rapamycin with different side effect profile. Aging research in early stages.

Limitations

Immunosuppression concerns; limited aging-specific data; dosing optimization needed

Biomarker targets

• mTOR activity
• Immune senescence
• Autophagy markers

Research summary

One of the most reproducible NIA ITP compounds in male mice; improves metabolic health without feminization. No human aging data.

Limitations

Male-specific effect in animals; no human trials; mechanism still being mapped.

Biomarker targets

• Fasting insulin
• IGF-1
• Inflammatory markers

Key references

• Harrison et al., Aging Cell 2014 — 17α-estradiol extends male mouse lifespan (ITP)

Research summary

Human trials confirm NAD+ elevation and some metabolic/physical-function signals; downstream clinical benefit remains modest and inconsistent.

Limitations

Bioavailability and optimal dose debated; regulatory status shifting; long-term outcomes unproven.

Biomarker targets

• NAD+/NADH ratio
• Insulin sensitivity

Key references

• Yoshino et al., Science 2021 — NMN improves insulin sensitivity in prediabetic women

Research summary

Consistently elevates NAD+ in humans and lowers some inflammatory markers; hard clinical endpoints (function, disease) remain to be demonstrated.

Limitations

NAD+ elevation has not translated to clear outcome benefits in trials to date.

Biomarker targets

• NAD+ metabolome
• hs-CRP

Key references

• Martens et al., Nat Commun 2018 — NR is well tolerated and raises NAD+

Research summary

RCTs report improved muscle endurance and mitochondrial gene expression in older adults; effect sizes are modest but reproducible.

Limitations

Depends on supplementation (variable endogenous production); clinically meaningful benefit still being defined.

Biomarker targets

• Mitochondrial function
• 6-min walk

Key references

• Singh et al., JAMA Netw Open 2022 — Urolithin A improves muscle endurance in older adults

Research summary

Clinical trials show mitochondrial benefits in specific conditions. Aging applications under investigation.

Limitations

Delivery challenges; high cost; limited aging-specific data

Biomarker targets

• Mitochondrial function
• Cardiac performance
• Exercise tolerance

Research summary

Improved vascular function in a small human trial; broader aging endpoints limited to preclinical data.

Limitations

Antioxidant strategies have a mixed track record; sparse human outcome data.

Biomarker targets

• Endothelial function
• Oxidative stress

Key references

• Rossman et al., Hypertension 2018 — MitoQ improves endothelial function

Research summary

Compressed morbidity and modestly extended lifespan in mice; a human study reported reduced DNAm age, awaiting replication.

Limitations

Single small human study; needs independent confirmation.

Biomarker targets

• DNAm age
• Inflammatory panel

Key references

• Asadi Shahmirzadi, Cell Metab 2020 — AKG extends lifespan/compresses morbidity in mice

Research summary

Preclinical CD38 inhibition raises tissue NAD+ and improves metabolic function; human evidence is indirect and early.

Limitations

Bioavailability; CD38 has essential immune roles; no human aging outcomes.

Biomarker targets

• NAD+/NADH
• CD38 activity

Key references

• Camacho-Pereira, Cell Metab 2016 — CD38 drives age-related NAD+ decline

Research summary

The KiSel-10 trial (CoQ10 + selenium) reduced cardiovascular mortality in older adults; broader anti-aging benefit is modest and context-dependent.

Limitations

Benefit clearest in deficiency and heart failure; general longevity effect small.

Biomarker targets

• Oxidative stress
• Ejection fraction

Key references

• Alehagen et al., 2013 (KiSel-10) — CoQ10 + selenium and cardiovascular mortality

Research summary

Popular in longevity clinics, but controlled evidence that IV NAD+ improves aging outcomes is essentially absent and its pharmacokinetics are debated.

Limitations

Little rigorous human data; cost; infusion discomfort; largely unregulated clinic use.

Biomarker targets

• NAD+ metabolome

Research summary

Cancer treatment experience provides safety data. Aging applications theoretical.

Limitations

Cancer risk considerations; dosing for healthy populations unknown; long-term effects unclear

Biomarker targets

• NAD+ preservation
• DNA repair
• Cellular energy

Research summary

Limited human studies show cognitive benefits. Research expanding to aging applications.

Limitations

Limited human data; optimal dosing unclear; mechanisms not fully understood

Biomarker targets

• Mitochondrial density
• Cognitive function
• Energy metabolism

Research summary

Human trials show favorable effects on inflammation and metabolic markers; a broadly beneficial dietary-derived modulator.

Limitations

Bioavailability varies widely with formulation; aging-specific outcomes limited.

Biomarker targets

• NRF2 targets
• hs-CRP

Research summary

Small human trials in older adults report improved oxidative stress, mitochondrial function, strength and cognition.

Limitations

Small, single-group studies; larger controlled replication needed.

Biomarker targets

• Glutathione
• Oxidative stress
• Gait speed

Key references

• Kumar et al., J Gerontol 2023 — GlyNAC supplementation in older adults

Research summary

Human trials show metabolic benefits. Development for aging applications continues.

Limitations

Development discontinued by original sponsor; safety profile incomplete

Biomarker targets

• SIRT1 activity
• Glucose metabolism
• Mitochondrial function

Research summary

Once heavily hyped; human trials are largely disappointing or inconsistent for longevity endpoints despite metabolic signals.

Limitations

Poor bioavailability; contested mechanism; weak and conflicting human data.

Biomarker targets

• SIRT1 activity
• Insulin sensitivity

Research summary

Butyrate and HDAC inhibition improve metabolic and cognitive markers in animal models; human evidence is early and largely indirect (via fiber/microbiome for butyrate) or extrapolated from oncology experience for the drugs.

Limitations

Delivery and dosing unclear; pharmacologic HDAC inhibitors carry oncology-derived toxicity; aging-specific human data minimal.

Biomarker targets

• SCFA levels
• Gut permeability
• Epigenetic age
• Gene expression

Research summary

Deficiency accelerates epigenetic dysregulation, and correction supports methylation — but supra-normal dosing has unclear or mixed effects.

Limitations

Benefit mainly in deficiency; over-supplementation may harm; aging endpoints indirect.

Biomarker targets

• Homocysteine
• SAM/SAH
• DNAm age

Research summary

Preclinical data suggest potential for epigenetic rejuvenation; human translation not yet established.

Limitations

Off-target effects and stability of changes remain concerns; dosing frameworks under development

Biomarker targets

• DNAm clocks
• Gene expression
• Cell identity

Research summary

Higher VO₂max maps to dramatically lower mortality with no observed ceiling; the single most evidence-backed longevity intervention.

Limitations

Requires sustained training; genetic ceiling on trainability; injury risk if progressed poorly.

Biomarker targets

• VO₂max
• Resting HR
• HRV

Key references

• Mandsager et al., JAMA Netw Open 2018 — Fitness and long-term mortality

Research summary

Strength and muscle mass independently predict survival and functional independence in older adults.

Limitations

Adherence and technique; slower gains with age; needs progressive overload to matter.

Biomarker targets

• Grip strength
• Lean mass
• Fasting insulin

Key references

• Li et al., 2018 meta-analysis — Muscle strength and mortality

Research summary

Both short and long sleep associate with higher mortality; sleep quality strongly influences cardiometabolic and cognitive aging.

Limitations

Confounded by illness; sleep is a modifiable driver and a marker of underlying health.

Biomarker targets

• Sleep efficiency
• HRV
• Glucose variability

Research summary

PREDIMED and other RCTs link the pattern to reduced cardiovascular events and mortality; among the best-supported dietary strategies.

Limitations

Pattern-level evidence; individual component effects harder to isolate; adherence-dependent.

Biomarker targets

• ApoB
• hs-CRP
• HbA1c

Key references

• PREDIMED, NEJM 2018 — Mediterranean diet and cardiovascular prevention

Research summary

Improves some cardiometabolic markers in trials; weight-independent benefits and optimal window remain debated.

Limitations

Results inconsistent across studies; risk of undereating protein; not superior to calorie control in some RCTs.

Biomarker targets

• Fasting insulin
• Glucose variability

Research summary

Large Finnish cohorts link frequent sauna use to lower cardiovascular and all-cause mortality; plausible hormetic mechanism.

Limitations

Observational cohorts risk confounding; RCT outcome data limited.

Biomarker targets

• Blood pressure
• HSP expression

Key references

• Laukkanen et al., JAMA Intern Med 2015 — Sauna use and mortality

Research summary

Meta-analyses link social integration to substantially lower mortality — effect sizes rivaling classic risk factors; purpose independently predicts reduced mortality.

Limitations

Observational; reverse causation and confounding; difficult to prescribe or dose.

Biomarker targets

• hs-CRP
• IL-6
• Cortisol rhythm

Key references

• Holt-Lunstad et al., PLoS Med 2010 — Social relationships and mortality risk

Research summary

WHO estimates 12.6M deaths/year from environmental factors. PM2.5 exposure accelerates epigenetic aging. Endocrine disruptors linked to metabolic syndrome and reproductive aging.

Limitations

Difficult to isolate individual toxin effects; ubiquitous exposure; individual detoxification capacity varies

Biomarker targets

• Heavy metal levels
• Endocrine function
• Oxidative stress
• Epigenetic age

Research summary

Improves insulin sensitivity and brown-fat activity in small studies; a longevity benefit in humans is inferred rather than demonstrated.

Limitations

Small studies; cardiovascular caution; longevity endpoints untested; enthusiasm exceeds evidence.

Biomarker targets

• Brown-fat activity
• Insulin sensitivity

Research summary

Longeveron's CRATUS trials in aging frailty showed improved physical performance, lower TNF-α and better quality of life with a good safety profile.

Limitations

Cell-source variability; standardization and potency challenges; unclear durability; high cost; regulatory complexity.

Biomarker targets

• Frailty index
• TNF-α
• 6-min walk

Key references

• Tompkins et al., J Gerontol 2017 — CRATUS: allogeneic MSCs in aging frailty

Research summary

The TRIIM pilot (GH + DHEA + metformin) reported thymic regrowth and a reversal of epigenetic age in a small cohort; TRIIM-X is the larger follow-up.

Limitations

Very small original cohort; GH carries metabolic/oncologic considerations; awaiting replication.

Biomarker targets

• Naive T-cells
• DNAm age

Key references

• Fahy et al., Aging Cell 2019 — TRIIM: thymic regeneration and epigenetic age reversal

Research summary

Preclinically promising for tissue repair and immunomodulation; human clinical evidence is early and quality-control is a major hurdle.

Limitations

No standardized potency assays; largely unregulated market; scant controlled human data.

Biomarker targets

• Inflammatory markers

Research summary

Heterochronic parabiosis and dilution studies motivate human interest; small human trials (e.g., Alzheimer's-adjacent) are exploratory.

Limitations

Invasive; benefit and durability unproven for healthy aging; mechanism debated.

Biomarker targets

• Inflammatory panel
• Cognitive scores

Research summary

Research shows aged HSCs accumulate mutations (CHIP) linked to cardiovascular disease and cancer. Approaches to rejuvenate HSC pools include young niche factors and selective elimination of mutant clones.

Limitations

Early-stage research; CHIP targeting may have unintended effects; complex bone marrow niche interactions poorly understood

Biomarker targets

• Immune diversity
• CHIP mutations
• Blood cell ratios
• Immune function

Research summary

CANTOS showed reduced cardiovascular events and, unexpectedly, lower lung-cancer incidence — establishing inflammation as a causal aging driver.

Limitations

Increased serious-infection risk; cost; net-benefit population selection required.

Biomarker targets

• hs-CRP
• IL-6
• IL-1β

Key references

• Ridker et al., NEJM 2017 — CANTOS: anti-inflammatory therapy and CV events

Research summary

LoDoCo2 and related RCTs show reduced cardiovascular events, offering a low-cost route to targeting inflammaging.

Limitations

GI intolerance; narrow therapeutic index; drug interactions; not an aging-endpoint trial.

Biomarker targets

• hs-CRP
• NLRP3 activity

Key references

• LoDoCo2, NEJM 2020 — Colchicine in chronic coronary disease

Research summary

DO-HEALTH and other trials suggest modest reductions in biological aging and infection; cardiovascular outcome data are mixed by formulation.

Limitations

Heterogeneous trial results; dose and formulation (EPA vs mixed) matter; effects modest.

Biomarker targets

• Omega-3 index
• hs-CRP
• IL-6

Key references

• DO-HEALTH, Nat Aging 2024 — Omega-3, vitamin D, exercise and aging

Research summary

Anti-inflammatory and metabolic signals in small human trials; bioavailability is the central limitation.

Limitations

Poor absorption without enhancers; small studies; risk of publication bias.

Biomarker targets

• hs-CRP
• IL-6

Research summary

A pasteurized-Akkermansia RCT improved insulin sensitivity and metabolic markers in overweight adults; abundance declines with age and metabolic disease.

Limitations

Single main RCT; strain and viability effects; durability of colonization uncertain.

Biomarker targets

• Gut permeability
• Insulin sensitivity

Key references

• Depommier et al., Nat Med 2019 — Pasteurized A. muciniphila in humans

Research summary

Consistent metabolic and inflammatory benefits across trials; a low-risk foundational intervention for gut-aging.

Limitations

Effects are gradual and pattern-level; individual microbiome variation shapes response.

Biomarker targets

• SCFA levels
• hs-CRP
• Microbiome diversity

Research summary

Centenarian studies show distinct microbiome signatures with higher Akkermansia and bile acid-producing bacteria. FMT from young to old mice extends lifespan. Prebiotics and probiotics show modest benefits in human aging.

Limitations

Individual microbiome variation enormous; causality vs correlation unclear; FMT standardization challenges; dietary confounders

Biomarker targets

• Microbiome diversity
• LPS levels
• Intestinal permeability
• SCFA production
• Akkermansia abundance

Research summary

Heterochronic FMT reverses some aging phenotypes in mice; human aging use is experimental beyond approved C. difficile indications.

Limitations

Safety screening critical; durability variable; aging benefit unproven in humans.

Biomarker targets

• Microbiome diversity
• Inflammatory panel

Research summary

TRAVERSE established cardiovascular safety in hypogonadal men; benefits are clearest for correcting genuine deficiency, not supraphysiologic use.

Limitations

Requires true deficiency; fertility, hematocrit and prostate monitoring; not a general anti-aging tool.

Biomarker targets

• Free testosterone
• Hematocrit
• PSA

Key references

• TRAVERSE, NEJM 2023 — Testosterone and cardiovascular safety

Research summary

Supplementation (0.5-5mg) improves sleep quality and may reduce age-related neurodegeneration. Animal studies show lifespan extension. Anti-cancer properties documented in several studies.

Limitations

Optimal dosing unclear (physiological vs pharmacological); morning grogginess at higher doses; quality control of supplements varies; long-term supplementation data limited

Biomarker targets

• Sleep quality
• Circadian rhythm
• Oxidative stress
• Immune function
• Neuroprotection

Research summary

Modest effects on body composition and bone in some trials; overall longevity benefit remains weak and inconsistent.

Limitations

Converts to sex steroids (variable, sex-dependent); small effect sizes; long-term data limited.

Biomarker targets

• DHEA-S
• Bone density

Research summary

Used in the TRIIM thymic-regeneration pilot; however, reduced GH/IGF-1 signaling is associated with longevity, making chronic GH use controversial.

Limitations

Insulin resistance, edema and potential cancer-promotion concerns; conflicts with low-IGF-1 longevity signal.

Biomarker targets

• IGF-1
• Fasting glucose
• Lean mass

Research summary

Subclinical dysfunction affects cardiometabolic and cognitive aging; interestingly, slightly lower thyroid function associates with exceptional longevity.

Limitations

Over-treatment risks bone and cardiac harm; 'optimal' range for longevity debated.

Biomarker targets

• TSH
• Free T3/T4